Pramipexole (I) is a dopamine D2 receptor agonist useful in treatment of Parkinson's disease. Pramipexole as its dihydrochloride salt is commercially available as Mirapex® tablets of Pharmacia & Upjohn. These are immediate-release tablets in 0.125 mg, 0.25 mg, 0.5 mg, 1.0 mg and 1.5 mg strengths, designed for oral administration of a single tablet three times per day to provide a daily dose of 0.375 to 4.5 mg. See Physicians' Desk Reference 57th edition (2003), 2768-2772. Doses herein are expressed in amounts of pramipexole dihydrochloride monohydrate unless otherwise specified; 1.0 mg pramipexole dihydrochloride monohydrate is equivalent to about 0.7 mg pramipexole base.

A three times daily dosing regimen for immediate-release pramipexole dihydrochloride tablets is well tolerated, but patient compliance would be much improved if a once-daily regimen were possible. In this regard, it will be noted that the primary indication for the drug, Parkinson's disease, is an affliction that becomes more prevalent with advancing age and is often accompanied by decline in memory. A once-daily regimen would be especially useful in enhancing compliance among elderly patients.
In common with other anti-Parkinson's disease drugs, pramipexole has potential to cause undesirable side effects. Side effects of pramipexole have been reported to include orthostatic hypotension, the incidence of which is dose-related. There are also reports of subjects on pramipexole medication experiencing increased somnolence, in particular “sleep attacks”. Such attacks involve a subject falling asleep while engaged in activities of daily living, including operation of a motor vehicle, sometimes resulting in accidents. Development of a new once-daily dosage form of pramipexole must take into account the potential to cause such side effects, so that the new dosage form, administered once daily, can be tolerated at least as well as the present immediate-release tablet formulation, administered three times daily.
It is an object of the present invention to provide a once-daily dosage form of pramipexole suitable for oral administration. It is a further object to provide such a dosage form having potential for side effects no greater than a three times daily regimen of pramipexole immediate release tablets. It is a still further object to identify an in vitro release profile that would be characteristic of a well tolerated once-daily dosage form of pramipexole. It is a still further object to identify an in vivo pharmacokinetic (PK) profile that would be consistent with good therapeutic efficacy while not causing an unacceptable incidence or severity of side effects. It is a still further object to provide exemplary dosage forms exhibiting such an in vitro release and/or in vivo PK profile.
Sustained release formulations of many drugs have been described in the literature. For example, U.S. Pat. No. 6,197,339 discloses a sustained-release tablet comprising (R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4,5-ij]-quinolin-2(1H)-one (Z)-2-butenedioate (1:1) (the dopamine D2 receptor agonist sumanirole maleate) in a matrix comprising hydroxypropylmethylcellulose (HPMC) and starch. The tablet is disclosed to be useful in treatment of Parkinson's disease. Starches disclosed to be suitable therein include pregelatinized starch.
U.S. Pat. No. 5,458,887 discloses a controlled-release tablet comprising an osmotic core that consists of a drug in admixture with a water-swellable component such as HPMC or polyethylene oxide, and a coating that comprises a water-resistant polymer and a minor amount of a water-soluble compound that acts as a pore-former. Upon formation of pores in the coating by dissolution of the water-soluble compound, the water-swellable agent is said to expand the core and provide a drug-rich surface in contact with gastrointestinal fluid.
U.S. Pat. No. 5,656,296 discloses a dual control sustained-release formulation comprising a core that comprises a drug and a low melting point excipient, and a coating layer over the core that comprises a pH-independent water-insoluble polymer and a water-soluble film-forming polymer.
European Patent Application No. EP 0 933 079 discloses a starch said to be suitable for preparing tablets having high hardness yet being capable of rapid disintegration in an aqueous medium. Tensile strength of the finished tablets is calculated from the hardness.
Hubble et al. (1995), Clinical Neuropharmacology 18(4), 338-347, described efficacy, safety, tolerability and pharmacokinetics of pramipexole administered three times a day in patients with early Parkinson's disease. A review of pramipexole use in management of early and advanced Parkinson's disease has been published by Dooley & Markham (1998), Drugs & Aging 12(6), 495-514. No disclosure is made therein of once-daily administration or sustained-release formulation of pramipexole.
More recently, Biglan & Holloway (2002), Expert Opinion on Pharmacotherapy 3(2), 197-210, reviewed pramipexole and its clinical utility in Parkinson's disease and noted that daily dosing with Mirapex® tablets is recommended in patients with impaired renal function, as evidenced by creatine clearance of 15-34 ml/minute. They also indicated that while dopamine receptor agonists generally have been associated with orthostatic hypotension, pramipexole does not appear to cause this complication any more than placebo in randomized controlled trials. It is reported therein, however, that evidence from such trials supports increased incidence of somnolence in patients receiving pramipexole in early Parkinson's disease.
Steady-state PK properties of pramipexole, administered three times a day in the form of pramipexole dihydrochloride tablets, were reported by Wright et al. (1997), Journal of Clinical Pharmacology 37, 520-525, who concluded that steady-state PK characteristics were linear up to a daily dose of 4.5 mg, for both men and women.
Patents and publications cited above are incorporated herein by reference.